Process for making hydroxylated cyclopentylpyrimidine compounds

ABSTRACT

The invention provides processes for preparing a compound of formula I 
                         
and salts thereof, wherein R 1  is defined herein, and compounds and intermediates of said formula.

PRIORITY OF INVENTION

This application is a divisional of U.S. patent application Ser. No.14/401,087, filed Nov. 13, 2014, which is a 35 U.S.C. 371 national stageapplication of International Patent Application No. PCT/US2013/041666,filed on May 17, 2013, and claims priority to U.S. ProvisionalApplication No. 61/648,473, filed on May 17, 2012 and U.S. ProvisionalApplication No. 61/785,122, filed on Mar. 14, 2013, all of which areincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

Disclosed herein are processes for making and purifyingcyclopentylpyrimidine compounds with therapeutic activity, againstdiseases such as cancer, as inhibitors of AKT kinase activity.

BACKGROUND OF THE INVENTION

The Protein Kinase B/Akt enzymes are a group of serine/threonine kinasesthat are overexpressed in certain human tumors. International PatentApplication Publication Number WO 2008/006040 and U.S. Pat. No.8,063,050 discuss a number of inhibitors of AKT, including the compound(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one(GDC-0068). While processes described in WO 2008/006040 and U.S. Pat.No. 8,063,050 are useful in providing hydroxylatedcyclopenta[d]pyrimidine compounds as AKT protein kinase inhibitors,alternative or improved processes are needed, including for large scalemanufacturing of these compounds.

BRIEF SUMMARY OF THE INVENTION

Disclosed are processes for preparing, separating and purifyingcompounds detailed herein. Compounds provided herein include AKT proteinkinase inhibitors, salts thereof, and intermediates useful in thepreparation of such compounds.

One aspect includes a process that includes cyclizing a compound offormula II

or a salt thereof, to form a compound of formula I

or a salt thereof, wherein:

-   -   R¹ is hydrogen or an amino protecting group;    -   R² is —CN, —COOR^(a) or —CONR^(a)R^(b);    -   R^(a) and R^(b) are independently hydrogen, —OR^(c), substituted        or unsubstituted C₁₋₁₂ alkyl, substituted or unsubstituted C₂₋₁₂        alkenyl, substituted or unsubstituted C₂₋₁₂ alkynyl, substituted        or unsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted        phenyl or substituted or unsubstituted 3 to 12 membered        heterocyclyl; or    -   R^(a) and R^(b) are taken together with the atom to which they        are attached to form a 3-7 membered heterocyclyl;    -   R^(c) is independently hydrogen or optionally substituted C₁₋₁₂        alkyl; and    -   M is Li or Mg.

Another aspect includes a process that includes contacting a compound offormula III, or a salt thereof, with a magnesium or lithium metalatingagent:

wherein R³ is bromo or iodo; to form the compound of formula I or a saltthereof.

Another aspect includes a process that includes contacting a compound offormula IV

or a salt thereof, with a compound

or salt thereof, wherein Lv is a leaving group, and each R³ isindependently iodo or bromo, to form the compound of formula III or asalt thereof.

Another aspect includes a process that includes brominating oriodinating a compound of formula V

or a salt thereof, wherein R⁴ is —Cl or —OH, to form a compound offormula IV.

Another aspect includes a compound of formula II

or a salt thereof, wherein:

-   -   R¹ is hydrogen or an amino protecting group;    -   R² is —CN, —COOR^(a) or —CONR^(a)R^(b);    -   R^(a) and R^(b) are independently hydrogen, —OR^(c), substituted        or unsubstituted C₁₋₁₂ alkyl, substituted or unsubstituted C₂₋₁₂        alkenyl, substituted or unsubstituted C₂₋₁₂ alkynyl, substituted        or unsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted        phenyl or substituted or unsubstituted 3 to 12 membered        heterocyclyl; or    -   R^(a) and R^(b) are taken together with the atom to which they        are attached to form a 3-7 membered heterocyclyl;    -   R^(c) is independently hydrogen or optionally substituted C₁₋₁₂        alkyl; and    -   M is Li or Mg.

Another aspect includes a compound of formula III

or a salt thereof, wherein:

-   -   R¹ is hydrogen or an amino protecting group;    -   R² is —CN, —COOR^(a) or —CONR^(a)R^(b);    -   R^(a) and R^(b) are independently hydrogen, —OR^(b), substituted        or unsubstituted alkyl, substituted or unsubstituted alkenyl,        substituted or unsubstituted alkynyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted phenyl or        substituted or unsubstituted heterocyclyl; or    -   R^(a) and R^(b) are taken together with the atom to which they        are attached to form a 3-7 membered heterocyclyl; and    -   R³ is bromo or iodo.

Another aspect includes a compound of formula IV

or a salt thereof, wherein:

-   -   R² is —CN, —COOR^(a) or —CONR^(a)R^(b); and each R³ is        independently iodo or bromo.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. While the invention will be described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments. Onthe contrary, the invention is intended to cover all alternatives,modifications, and equivalents which may be included within the scope ofthe present invention as defined by the claims. One skilled in the artwill recognize many methods and materials similar or equivalent to thosedescribed herein, which could be used in the practice of the presentinvention. The present invention is in no way limited to the methods andmaterials described. In the event that one or more of the incorporatedliterature and similar materials differs from or contradicts thisapplication, including but not limited to defined terms, tem usage,described techniques, or the like, this application controls.

“Acyl” means a carbonyl containing substituent represented by theformula —C(O)—R in which R is hydrogen, alkyl, a cycloalkyl, aheterocyclyl, cycloalkyl-substituted alkyl or heterocyclyl-substitutedalkyl wherein the alkyl, alkoxy, cycloalkyl and heterocyclyl areindependently optionally substituted and as defined herein. Acyl groupsinclude alkanoyl (e.g., acetyl), aroyl (e.g., benzoyl), and heteroaroyl(e.g., pyridinoyl).

The term “alkyl” as used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of one to twelve carbonatoms, and in another embodiment one to six carbon atoms, wherein thealkyl radical may be optionally substituted independently with one ormore substituents described herein. Examples of alkyl groups include,but are not limited to, methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl(n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂),1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, butyl,—CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl, 1-octyl, and the like.

The term “alkylene” as used herein refers to a linear or branchedsaturated divalent hydrocarbon radical of one to twelve carbon atoms,and in another embodiment one to six carbon atoms, wherein the alkyleneradical may be optionally substituted independently with one or moresubstituents described herein. Examples include, but are not limited to,methylene, ethylene, propylene, 2-methylpropylene, pentylene, and thelike.

The term “alkenyl” as used herein refers to a linear or branched-chainmonovalent hydrocarbon radical of two to twelve carbon atoms, and inanother embodiment two to six carbon atoms, with at least one site ofunsaturation, i.e., a carbon-carbon, sp² double bond, wherein thealkenyl radical may be optionally substituted independently with one ormore substituents described herein, and includes radicals having “cis”and “trans” orientations, or alternatively, “E” and “Z” orientations.Examples include, but are not limited to, ethylenyl or vinyl (—CH═CH₂),allyl (—CH₂CH═CH₂), 1-propenyl, 1-buten-1-yl, 1-buten-2-yl, and thelike.

The term “alkynyl” as used herein refers to a linear or branchedmonovalent hydrocarbon radical of two to twelve carbon atoms, and inanother embodiment two to six carbon atoms, with at least one site ofunsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynylradical may be optionally substituted independently with one or moresubstituents described herein. Examples include, but are not limited to,ethynyl (—C≡CH) and propynyl (propargyl, —CH₂C≡CH).

The term “alkoxy” refers to a linear or branched monovalent radicalrepresented by the formula —OR in which R is alkyl, alkenyl, alkynyl orcycloalkyl, which can be further optionally substituted as definedherein. Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy,mono-, di- and tri-fluoromethoxy and cyclopropoxy.

“Amino” means primary (i.e., —NH₂), secondary (i.e., —NRH), tertiary(i.e., —NRR) and quaternary (i.e., —N⁺RRRX⁻) amines, that are optionallysubstituted, in which R is independently alkyl, alkoxy, a cycloalkyl, aheterocyclyl, cycloalkyl, -substituted alkyl or heterocyclyl-substitutedalkyl wherein the alkyl, alkoxy, cycloalkyl and heterocyclyl are asdefined herein Particular secondary and tertiary amines are alkylamine,dialkylamine, arylamine, diarylamine, aralkylamine and diaralkylaminewherein the alkyls and aryls are as herein defined and independentlyoptionally substituted. Particular secondary and tertiary amines aremethylamine, ethylamine, propylamine, isopropylamine, phenylamine,benzylamine dimethylamine, diethylamine, dipropylamine anddiisopropylamine.

The terms “cycloalkyl,” “carbocycle,” “carbocyclyl” and “carbocyclicring” as used herein are used interchangeably and refer to saturated orpartially unsaturated cyclic hydrocarbon radical having from three totwelve carbon atoms, and in another embodiment three to eight carbonatoms. The term “cycloalkyl” includes monocyclic and polycyclic (e.g.,bicyclic and tricyclic) cycloalkyl structures, wherein the polycyclicstructures optionally include a saturated or partially unsaturatedcycloalkyl ring fused to a saturated, partially unsaturated or aromaticcycloalkyl or heterocyclic ring. Examples of cycloalkyl groups include,but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,and the like. Bicyclic carbocycles include those having 7 to 12 ringatoms arranged, for example, as a bicyclo [4,5], [5,5], [5,6] or [6,6]system, or as bridged systems such as bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. The cycloalkyl may beoptionally substituted independently with one or more substituentsdescribed herein.

The term “aryl” as used herein means a monovalent aromatic hydrocarbonradical of 6-20 carbon atoms derived by the removal of one hydrogen atomfrom a single carbon atom of a parent aromatic ring system. Arylincludes bicyclic radicals comprising an aromatic ring fused to asaturated, partially unsaturated ring, or aromatic carbocyclic orheterocyclic ring. Exemplary aryl groups include, but are not limitedto, radicals derived from benzene, naphthalene, anthracene, biphenyl,indene, indane, 1,2-dihydronapthalene, 1,2,3,4-tetrahydronapthalene, andthe like. Aryl groups may be optionally substituted independently withone or more substituents described herein.

The terms “heterocycle”, “hetercyclyl” and “heterocyclic ring” as usedherein are used interchangeably and refer to a saturated or partiallyunsaturated carbocyclic radical of 3 to 12 membered ring atoms in whichat least one ring atom is a heteroatom independently selected fromnitrogen, oxygen and sulfur, the remaining ring atoms being C, where oneor more ring atoms may be optionally substituted independently with oneor more substituents described below. One embodiment includesheterocycles of 3 to 7 membered ring atoms in which at least one ringatom is a heteroatom independently selected from nitrogen, oxygen andsulfur, the remaining ring atoms being C, where one or more ring atomsmay be optionally substituted independently with one or moresubstituents described below. The radical may be a carbon radical orheteroatom radical. The term “heterocycle” includes heterocycloalkoxy.“Heterocyclyl” also includes radicals where heterocycle radicals arefused with a saturated, partially unsaturated, or aromatic carbocyclicor heterocyclic ring. Examples of heterocyclic rings include, but arenot limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl,thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl,4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl,dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl,pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyco[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolylquinolizinyl and N-pyridyl ureas. Spiro moieties are also includedwithin the scope of this definition. The heterocycle may be C-attachedor N-attached where such is possible. For instance, a group derived frompyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).Further, a group derived from imidazole may be imidazol-1-yl(N-attached) or imidazol-3-yl (C-attached). Examples of heterocyclicgroups wherein 2 ring carbon atoms are substituted with oxo (═O)moieties are isoindoline-1,3-dionyl and 1,1-dioxo-thiomorpholinyl. Theheterocycle groups herein are optionally substituted independently withone or more substituents described herein.

The term “heteroaryl” as used herein refers to a monovalent aromaticradical of a 5-, 6-, or 7-membered ring and includes fused ring systems(at least one of which is aromatic) of 5-10 atoms containing at leastone heteroatom independently selected from nitrogen, oxygen, and sulfur.Examples of heteroaryl groups include, but are not limited to,pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Spiromoieties are also included within the scope of this definition.Heteroaryl groups may be optionally substituted independently with oneor more substituents described herein.

“Leaving group” refers to a portion of a first reactant in a chemicalreaction that is displaced from the first reactant in the chemicalreaction. Examples of leaving groups include, but are not limited to,hydrogen, halogen, hydroxyl groups, sulfhydryl groups, amino groups (forexample —NRR, wherein R is independently alkyl, alkenyl, alkynyl,cycloalkyl, phenyl or heterocyclyl and R is independently optionallysubstituted), silyl groups (for example —SiRRR, wherein R isindependently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl orheterocyclyl and R is independently optionally substituted), —N(R)OR(wherein R is independently alkyl, alkenyl, alkynyl, cycloalkyl, phenylor heterocyclyl and R is independently optionally substituted), alkoxygroups (for example —OR, wherein R is independently alkyl, alkenyl,alkynyl, cycloalkyl, phenyl or heterocyclyl and R is independentlyoptionally substituted), thiol groups (for example —SR, wherein R isindependently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl orheterocyclyl and R is independently optionally substituted), sulfonyloxygroups (for example —OS(O)₁₋₂R, wherein R is independently alkyl,alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl and R isindependently optionally substituted), sulfamate groups (for example—OS(O)₁₋₂NRR, wherein R is independently alkyl, alkenyl, alkynyl,cycloalkyl, phenyl or heterocyclyl and R is independently optionallysubstituted), carbamate groups (for example —OC(O)₂NRR, wherein R isindependently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl orheterocyclyl and R is independently optionally substituted), andcarbonate groups (for example —OC(O)₂RR, wherein R is independentlyalkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl and R isindependently optionally substituted). Example sulfonyloxy groupsinclude, but are not limited to, alkylsulfonyloxy groups (for examplemethyl sulfonyloxy (mesylate group) and trifluoromethylsulfonyloxy(triflate group)) and arylsulfonyloxy groups (for examplep-toluenesulfonyloxy (tosylate group) and p-nitrosulfonyloxy (nosylategroup)). Other examples of leaving groups include substituted andunsubstituted amino groups, such as amino, alkylamino, dialkylamino,hydroxylamino, alkoxylamino, N-alkyl-N-alkoxyamino, acylamino,sulfonylamino, and the like.

“Amino-protecting group” as used herein refers to groups commonlyemployed to keep amino groups from reacting during reactions carried outon other functional groups. Examples of such protecting groups includecarbamates, amides, alkyl and aryl groups, imines, as well as manyN-heteroatom derivatives which can be removed to regenerate the desiredamine group. Particular amino protecting groups are Ac (acetyl),trifluoroacetyl, phthalimide, Bn (benzyl), Tr (triphenylmethyl ortrityl), benzylidenyl, p-toluenesulfonyl, Pmb (p-methoxybenzyl), Boc(tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl) and Cbz(carbobenzyloxy). Further examples of these groups are found in: Wuts,P. G. M. and Greene, T. W. (2006) Frontmatter, in Greene's ProtectiveGroups in Organic Synthesis, Fourth Edition, John Wiley & Sons, Inc.,Hoboken, N.J., USA. The term “protected amino” refers to an amino groupsubstituted with one of the above amino-protecting groups.

The term “substituted” as used herein means any of the above groups(e.g., alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyland heteroaryl) wherein at least one hydrogen atom is replaced with asubstituent. In the case of an oxo substituent (“═O”) two hydrogen atomsare replaced. “Substituents” within the context of this inventioninclude, but are not limited to, halogen, hydroxy, oxo, cyano, nitro,amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, cycloalkyl,alkoxy, substituted alkyl, thioalkyl, haloalkyl (includingperhaloalkyl), hydroxyalkyl, aminoalkyl, substituted alkenyl,substituted alkynyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocycle, substitutedheterocycle, —NR^(e)R^(f), —NR^(e)C(═O)R^(f), —NR^(e)C(═O)NR^(e)R^(f),—NR^(e)C(═O)OR^(f)NR^(e)SO₂R^(f), —OR^(e), —C(═O)R^(e)—C(═O)OR^(e),—C(═O)NR^(e)R^(f), —OC(═O)NR^(e)R^(f), —SR^(e), —SOR^(e), —S(═O)₂R^(e),—OS(═O)₂R^(e), —S(═O)₂OR^(e), wherein R^(e) and R^(f) are the same ordifferent and independently hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocycle, substituted heterocycle.

The term “halo” or “halogen” as used herein means fluoro, chloro, bromoor iodo.

The term “a” as used herein means one or more.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse and in one embodiment plus or minus 20% of the given value. Forexample, description referring to “about X” includes description of “X”.

“Pharmaceutically acceptable salts” include both acid and base additionsalts. Exemplary salts include, but are not limited, to sulfate,citrate, acetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Apharmaceutically acceptable salt may involve the inclusion of anothermolecule such as an acetate ion, a succinate ion or other counter ion.The counter ion may be any organic or inorganic moiety that stabilizesthe charge on the parent compound.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases and which are not biologically or otherwise undesirable, formedwith inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like,and organic acids may be selected from aliphatic, cycloaliphatic,aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes oforganic acids such as formic acid, acetic acid, propionic acid, glycolicacid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid,maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid,citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilicacid, benzoic acid, cinnamic acid, mandelic acid, embonic acid,phenylacetic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, salicyclic acid and thelike.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Particularly base addition salts are the ammonium, potassium,sodium, calcium and magnesium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases includes salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperizine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly organicnon-toxic bases are isopropylamine, diethylamine, ethanolamine,tromethamine, dicyclohexylamine, choline, and caffeine.

Compounds of the present invention, unless otherwise indicated, includecompounds that differ only in the presence of one or more isotopicallyenriched atoms. For example, compounds of the present invention, whereinone or more hydrogen atoms are replaced by deuterium or tritium, or oneor more carbon atoms are replaced by a ¹³C or ¹⁴C carbon atom, or one ormore nitrogen atoms are replaced by a ¹⁵N nitrogen atom, or one or moresulfur atoms are replaced by a ³³S, ³⁴S or ³⁶S sulfur atom, or one ormore oxygen atoms are replaced by a ¹⁷O or ¹⁸O oxygen atom are withinthe scope of this invention.

One aspect provides a process comprising cyclizing a compound of formulaII

or a salt thereof, to form a compound of formula I

or a salt thereof, wherein:

-   -   R¹ is hydrogen or an amino protecting group;    -   R² is —CN, —COOR^(a) or —CONR^(a)R^(b);    -   R^(a) and R^(b) are independently hydrogen, —OR^(c), substituted        or unsubstituted C₁₋₁₂ alkyl, substituted or unsubstituted C₂₋₁₂        alkenyl, substituted or unsubstituted C₂₋₁₂ alkynyl, substituted        or unsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted        phenyl or substituted or unsubstituted 3-12 membered        heterocyclyl; or    -   R^(a) and R^(b) are taken together with the atom to which they        are attached to form a 3-7 membered heterocyclyl;    -   R^(c) is independently hydrogen or optionally substituted C₁₋₁₂        alkyl; and    -   M is Li or Mg.

Another aspect includes the compound of formula I or a salt thereofproduced according to the process comprising cyclizing a compound offormula II or a salt thereof.

Another aspect provides a process comprising, contacting a compound offormula III

-   -   or a salt thereof, wherein:    -   R¹ is hydrogen or an amino protecting group;    -   R² is —CN, —COOR^(a) or —CONR^(a)R^(b);    -   R^(a) and R^(b) are independently hydrogen, —OR^(c), substituted        or unsubstituted C₁₋₁₂ alkyl, substituted or unsubstituted C₂₋₁₂        alkenyl, substituted or unsubstituted C₂₋₁₂ alkynyl, substituted        or unsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted        phenyl or substituted or unsubstituted 3 to 12 membered        heterocyclyl; or    -   R^(a) and R^(b) are taken together with the atom to which they        are attached to form a 3-7 membered heterocyclyl;    -   R^(c) is independently hydrogen or optionally substituted C₁₋₁₂        alkyl; and    -   R³ is bromo or iodo;        with a metalating agent comprising magnesium or lithium, to form        a compound of formula I or a salt thereof.

Another aspect includes the compound of formula I or II, or a saltthereof, produced according to the process comprising contacting acompound of formula III with a metalating agent comprising magnesium orlithium.

In another embodiment, the above processes further comprise contacting acompound of formula IV:

or a salt thereof, with a compound

or salt thereof, to form a compound of formula III wherein:

-   -   R¹ is hydrogen or an amino protecting group;    -   R² is —CN, —COOR^(a) or —CONR^(a)R^(b);    -   R^(a) and R^(b) are independently hydrogen, —OR^(c), substituted        or unsubstituted C₁₋₁₂ alkyl, substituted or unsubstituted C₂₋₁₂        alkenyl, substituted or unsubstituted C₂₋₁₂ alkynyl, substituted        or unsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted        phenyl or substituted or unsubstituted 3 to 12 membered        heterocyclyl; or    -   R^(a) and R^(b) are taken together with the atom to which they        are attached to form a 3-7 membered heterocyclyl;    -   R^(c) is independently hydrogen or optionally substituted C₁₋₁₂        alkyl; and    -   each R³ is independently bromo or iodo; and    -   Lv is a leaving group.

Another aspect includes the compound of formula III, or a salt thereof,produced according to the process comprising contacting a compound offormula IV or a salt thereof, with a compound

or salt thereof.

In another embodiment, the above processes further comprise brominatingor iodinating a compound of formula V

or a salt thereof to form a compound of formula IV or salt thereof,wherein R⁴ is —Cl or —OH.

In one embodiment, the above processes further comprise brominating acompound of formula V, or a salt thereof, wherein R⁴ is —OH.

In one embodiment, the above brominating further comprises contactingthe compound of formula V, or a salt thereof, with a brominating agentto form a compound of formula IV, or salt thereof, wherein R³ in formulaIV is Br.

Brominating agents include, for example, PBr₃, PBr₅, O═PBr₃, P(OH)Br₃,Br₂ (in one example with a phosphine, such as PR₃ wherein R is an alkyl,cycloalkyl, aryl or heterocyclyl group), HBr, O═SBr₂, other bromidesalts such as NaBr, KBr and CuBr₂ (in one example with fluorinatingagents such as 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) or Selectfluor®), and hexabromoacetone (in oneexample with an alkyltribromoacetate such as ethyltribromoacetate).

In one embodiment, the brominating agent comprises bromine andphosphorous, for example, PBr₃, PBr₅, O═PBr₃, P(OH)Br₃ and Br₂ incombination with a phosphine, such as PR₃ wherein R is an alkyl,cycloalkyl, aryl or heterocyclyl group.

In one embodiment, the above processes further comprise iodinating acompound of formula V, wherein R⁴ is —Cl.

In one embodiment, the above iodinating further comprises contacting thecompound of formula V, or a salt thereof, with an iodinating agent toform a compound of formula IV, or salt thereof, wherein R³ in formula IVis I.

Iodinating agents include, for example, salts of iodide, such as NaI, KIor HI (in one example, generated in situ from an iodide salt and acid,such as sodium or potassium iodide with acid such as methanesulfonicacid).

Another aspect includes the compound of formula IV, or a salt thereof,produced according to the process comprising brominating or iodinating acompound of formula V.

In certain embodiments, when R¹ of formula I is an amino protectinggroup, the process further comprises, deprotecting the amino protectinggroup to provide a compound of the formula I where R¹ is H. In oneexample, R¹ is tert-butoxycarbonyl (Boc) and the process furthercomprises removing the Boc group by contacting the compound of formula Iwith an acid, for example hydrochloric, sulfuric,trifluoromethanesulfonic, or trifluoroacetic acid.

In certain embodiments, R¹ is an amino protecting group, for example, aremovable carbamoyl group (e.g., tert-butoxycarbonyl andbenzyloxycarbonyl). In some embodiments, R¹ of formula (II) and/orformula (I) is a substituted acyl group such as a substituted—C(O)-alkyl.

In certain embodiments, R¹ is —C(O)—R^(d) or —C(O)OR^(d), and R^(d) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedphenyl or substituted or unsubstituted heterocyclyl.

In certain embodiments, R^(c) is C₁₋₆ alkyl or hydrogen, wherein saidalkyl is optionally substituted by oxo, halo or phenyl.

In certain embodiments, R^(d) is C₁₋₆ alkyl or hydrogen, wherein saidalkyl is optionally substituted by oxo, halo or phenyl. In certainembodiments, R^(d) is tert-butyl.

In certain embodiments, R¹ is hydrogen.

In certain embodiments, R² is —COOR^(a) or —CONR^(a)R^(b).

In certain embodiments, R² is —COOH or —COOCH₃.

In certain embodiments, R² is —C(O)N(R^(a))OR^(b). In certainembodiments, R² is —C(O)N(CH₃)OCH₃.

In certain embodiments, R² is —CN, —COOH or —CONR^(a)R^(b). In certainembodiments, R² is —COOMe or —COOEt. In certain embodiments, R² is—COOPr.

In certain embodiments, R^(a) and R^(b) are independently hydrogen,—OR^(c), substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted phenyl orsubstituted or unsubstituted heterocyclyl.

In certain embodiments, R^(a) and R^(b) are independently hydrogen, C₁₋₆alkyl or —O(C₁₋₆ alkyl).

In certain embodiments, R^(a) and R^(b) are taken together with the atomto which they are attached to form a 3-7 membered heterocyclyl.

In certain embodiments, R^(a) and R^(b) are independently hydrogen orC₁₋₆ alkyl, wherein said alkyl is optionally substituted by oxo, halo orphenyl.

In certain embodiments, R^(a) and R^(b) are methyl.

In certain embodiments, R^(a) and R^(b) are taken together with the atomto which they are attached to form a morpholinyl group.

In certain embodiments, M is Mg.

In certain embodiments, M is Li.

In certain embodiments, R³ is iodo. In another embodiment, R³ is bromo.

In certain embodiments, R⁴ is OH. In certain embodiments, R⁴ is Cl.

In some embodiments, the metalating agent comprises one or more oflithium and magnesium. In some embodiments, the metalating agent is anorganomagnesium compound such as a Grignard reagent (e.g., a C₁-C₆alkylmagnesium halide, for example, iPrMgCl.) In some embodiments, themetalating agent is an organolithium compound such as a C₁-C₆alkyllithium (e.g., n-butyllithium and t-butyllithium).

In some embodiments, the metalating agent is one or more of (i) LiR and(ii) MgR₂, wherein each R is independently halogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₇ cycloalkyl,optionally substituted aryl, optionally substituted heteroaryl, oroptionally substituted and heterocyclyl, or two R groups are takentogether with the atom to which they are attached to form a 5-7membered, optionally substituted ring. In some embodiments, each R isindependently halogen, optionally substituted C₁₋₆ alkyl or optionallysubstituted C₃₋₇ cycloalkyl.

In one aspect, the process for preparing a compound of formula I, or asalt thereof, from a compound of formulae II or III may be carried outin an ethereal or hydrocarbon solvent or a mixture of these solvents.(e.g., tetrahydrofuran (THF), methyl tert-butyl ether (MTBE),cyclopentyl methyl ether (CPME), diethyl ether, diisopropyl ether,diphenyl ether, toluene, ethylbenzene, xylene, cumene, pentane orheptane). Other suitable conditions may be used (e.g., reactiontemperature at or below 20° C., such as at about −10° C., or at about−78° C.), carrying out the reaction under substantially anhydrousconditions (for example, less than about 100 ppm, 50 ppm or less thanabout 10 ppm water), and carrying out the reaction under an inertatmosphere, for example, under a helium, neon, argon or nitrogenatmosphere). In a particular variation, a process for preparing acompound of formula I, or a salt thereof, from a compound of formulae IIor III is carried out under nitrogen atmosphere in THF at a temperatureof between about −25° C. and about −5° C., or at about −10±2° C., underanhydrous conditions.

In another embodiment, compounds of formula I are used in thepreparation of inhibitors of AKT kinase for treating diseases anddisorders responsive to the inhibition of AKT, as described in U.S. Pat.No. 8,063,050 to Mitchell, et al.

Another aspect includes a process of producing a compound of formula2.2, or salt thereof,

comprising reducing stereo selectively a compound of formula I, or saltthereof,

to form a compound of formula 2.1, or salt thereof,

and reacting the compound of formula 2.1 or salt thereof with a compoundof the formula

or salt thereof, to form a compound of formula 2.2.

Another aspect includes the compound of formula 2.2 or salt thereofproduced according to the process comprising reducing stereoselectivelya compound of formula I, or salt thereof, to form a compound of formula2.1, or salt thereof, and reacting the compound of formula 2.1 or saltthereof with a compound of the formula

or salt thereof.

The compounds detailed herein may contain one or more chiral centers.Accordingly, if desired, such compounds can be prepared or isolated aspure stereoisomers (such as individual enantiomers or diastereomers, oras stereoisomer-enriched mixtures). All such stereoisomers (and enrichedmixtures) are included within the scope of this invention, unlessotherwise indicated. Pure stereoisomers (or enriched mixtures) may beprepared using, for example, optically active starting materials orstereoselective reagents well-known in the art. Alternatively, racemicor stereoisomer-enriched mixtures of such compounds can be separatedusing, for example, chiral column chromatography, chiral resolvingagents, and the like.

For illustrative purposes, Scheme 1 shows a general method for preparingthe compounds of the present invention as well as key intermediates. Fora more detailed description of the individual reaction steps, see theExamples section below. Those skilled in the art will appreciate thatother synthetic routes may be used to synthesize the inventivecompounds. Although specific starting materials and reagents aredepicted in the Scheme and discussed below, other starting materials andreagents can be easily substituted to provide a variety of derivativesand/or reaction conditions. In addition, many of the compounds preparedby the methods described below can be further modified in light of thisdisclosure using conventional chemistry well known to those skilled inthe art.

Scheme 1 illustrates a method for making a compound of the formula I,where R¹, R^(a) and R^(b) are independently defined as above for formulaI. Reaction of compound 1.1 with an iodination agent (e.g., iodide salt,such as NaI and optionally with an acid), gives diiodopyrimidine 1.2,which reacts with a mono-protected piperazine to afford methyl ester1.3. The methyl ester is converted to an amide 1.5 via the acidintermediate 1.4 prepared by base hydrolysis of the ester. Amide 1.5 ismetalated with a metalating agent, such a Grignard reagent (e.g.,^(i)PrMgCl), and cyclized to form cyclopentyl ketone I.

Another aspect provides the use of compounds of formula I asintermediates for preparing pharmaceutically active compounds, such asthe AKT inhibitors described in U.S. Pat. No. 8,063,050, issued Nov. 22,2011 to Mitchell. For example, as shown below in Scheme 2, compounds offormula I can be used to prepare(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one,as described in U.S. Pat. No. 8,063,050, issued Nov. 22, 2011, asdescribed, for example, in Example 14, which is incorporated herein byreference.

Scheme 2 illustrates a method for making a compound of formula 2.2.Asymmetric reduction of compounds of formula I give compounds of formula2.1, wherein R¹ defined above for formula I. When R¹ is a protectinggroup, for example a Boc group, compound 2.1 can then be reacted withHCl, acylated and functionalized, for example by further deprotection,to give compound 2.2.

Another aspect includes a product produced by any process, scheme orexample provided herein.

EXAMPLES

The invention can be further understood by reference to the followingexamples, which are provided by way of illustration and are not meant tobe limiting.

Abbreviations used herein are as follows:

Aq.: aqueous

DIPA: diisopropylamine

DIPEA: diisopropylethylamine

MTBE: methyl t-butyl ether

TMSCl: chlorotrimethylsilane

MsDPEN: N-methanesulfonyl-1,2-diphenylethylenediamine

TsDACH: N-(p-toluenesulfonyl)-1,2-diaminocyclohexane

Dppp: 1,3-Bis(diphenylphosphino)propan

NMM: 4-methylmorpholine

PhME: toluene

CPME: Cyclopentyl methyl ether

DBU: 1,8-Diazobicyclo[5,40]undec-7-ene

CDI: 1,1′-carbonyldiimidazole

Example 1

(R)-methyl 3-(4,6-dichloropyrimidin-5-yl)butanoate

Into a mixture of (R)-methyl 3-(4,6-dihydroxypyrimidin-5-yl)butanoate(1.00 kg, 4.70 mol), toluene (4.00 L), and 2,6-lutidine (0.550 L, 4.70mol) was added phosphorous oxychloride (0.960 L, 10.6 mol) at 50° C.slowly. The mixture was stirred at 70° C. for 24 h. The solution wascooled to 0° C. To the mixture was slowly added 20% aqueous sodiumhydroxide (about 40.0 mol, 1.60 kg in 8.00 L H₂O) while maintaining theinternal temperature below 30° C., to obtain a final pH value between 5and 6. Ethyl acetate (2.50 L) was added, stirred for 0.5 h, and then thelayers were separated. The aqueous phase was extracted with ethylacetate (3×1.00 L). The organics were combined and washed with 1 Nhydrochloric acid (2×2.50 L), and brine (2.50 L). The organic layerswere combined and dried over sodium sulfate and filtered through a glassfiber filter. The solution was concentrated to about 3.00 mL/g, anddiluted with acetonitrile to about 7.00 mL/g. The sequence was repeatedtwo times to remove residue ethyl acetate and toluene (confirmed by ¹HNMR analysis). The remaining crude solution was used directly for nextstep without further purification or isolation. ¹H NMR (300 MHz, CDCl₃)δ 8.62 (s, 1H), 4.15 (ddq, J=8.1, 7.2, 7.2 Hz, 1H), 3.64 (s, 3H), 3.08(dd, J=16.5, 8.1 Hz, 1H), 2.86 (dd, J=16.5, 7.2 Hz, 1H), 1.45 (d, J=7.2Hz, 3H). HRMS calcd. For C₉H₁₁Cl₂N₂O₂ [M+H]+: 249.0192. found 249.0190.

Example 2

(R)-methyl 3-(4,6-diiodopyrimidin-5-yl)butanoate

Into a solution of (R)-methyl 3-(4,6-dichloropyrimidin-5-yl)butanoate(36.0 g, 145 mmol) in acetonitrile (540 mL) was added sodium iodide (152g, 1.02 mol). The mixture was stirred at 25° C. for 30 min and thencooled to about 5° C. Methanesulfonic acid (9.41 mL, 1.00 equiv) wasadded over 5 min. The mixture was agitated at about 5° C. for 3 h. Thereactor was cooled to about 5° C. and N,N-diisopropylethylamine (20.3mL, 116 mmol) was added. The mixture was agitated for 1 h while warmingthe mixture to 20° C. Saturated sodium sulfite solution was added untilno further color change was observed to remove the iodine. Water (540mL) was added and the pH was adjusted to between about 5 and 7. Thebiphasic mixture was concentrated under reduced pressure at atemperature of less than 40° C. to remove acetonitrile. The aqueoussuspension was filtered to give 48.8 g (78% yield) of off-white solidproduct. ¹H NMR (300 MHz, CDCl₃) δ 8.21 (s, 1H), 4.02 (ddq, J=7.8, 7.5,7.2 Hz, 1H), 3.67 (s, 3H), 3.18 (dd, J=16.5, 7.8 Hz, 1H), 2.91 (dd,J=16.5, 7.5 Hz, 1H), 1.47 (d, J=7.2 Hz, 3H). HRMS calcd. For C₉H₁₁I₂N₂O₂[M+H]+: 432.8904. found 432.8906.

Example 3

(R)-tert-butyl4-(6-iodo-5-(4-methoxy-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate

Into a solution of (R)-methyl 3-(4,6-diiodopyrimidin-5-yl)butanoate (212g, 491 mmol) and Boc-piperazine (101 g, 540 mmol) in methanol (424 mL)was added N,N-diisopropylethylamine (94.3 mL, 540 mmol). The mixture washeated at 60° C. for 24 h. Methanol was distilled off under reducedpressure below 40° C. To the mixture was added 318 mL oftetrahydrofuran. The above solvent swap process was repeated twice. Tothe mixture were added 424 mL of tetrahydrofuran, 212 mL of saturatedaqueous ammonium chloride, and 21.2 mL of water. The organic layer waswashed with 212 mL (1.00 vol.) of saturated aqueous ammonium chloride.This tetrahydrofuran solution was used for next step without furtherpurification (91% weight assay yield). ¹H NMR (300 MHz, CDCl₃) δ 8.25(s, 1H), 3.80-3.67 (m, 1H), 3.65 (s, 3H), 3.60-3.56 (m, 4H), 3.21-3.18(m, 4H), 3.14 (dd, J=16.2, 9.0 Hz, 1H), 2.81 (dd, J=16.2, 5.7 Hz, 1H),1.48 (s, 9H), 1.47 (d, J=7.2 Hz, 3H). HRMS calcd. For C₁₈H₂₈IN₄O₄[M+H]+: 491.1150. found 491.1154.

Example 4

(R)-3-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-iodo-pyrimidin-5-yl)butanoicacid

Into a solution of (R)-tert-butyl4-(6-iodo-5-(4-methoxy-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate(219 g, 0.447 mol) in tetrahydrofuran (657 mL) was added a solution oflithium hydroxide monohydrate (56.2 g, 1.34 mol) in 329 mL of water at25° C. The mixture was stirred at 25° C. for 5 h. The bottom aqueouslayer was discarded. The mixture was acidified with 1 N hydrochloricacid at 5° C. to give a final pH value of between about 1 to 2. Thelayers were separated. The top layer was then extracted with isopropylacetate (440 mL×3), combined with the bottom layer, and washed withwater (220 mL×2). The solvents was distilled off at reduced pressurebelow 50° C. The residual isopropyl acetate was azeotroped off withheptane under reduced pressure below 50° C. Product graduallyprecipitated out and was filtered to give an off-white to light yellowpowder (196 g, 84% yield). ¹H NMR (300 MHz, CDCl₃) δ 8.27 (s, 1H),3.80-3.68 (m, 1H), 3.59-3.56 (m, 4H), 3.23-3.14 (m, 5H), 2.86 (dd,J=16.5, 5.4 Hz, 1H), 1.50 (d, J=7.2 Hz, 3H), 1.48 (s, 9H). HRMS calcd.For C₁₇H₂₆IN₄O₄ [M+H]+: 477.0993. found 477.0995.

Example 5

(R)-tert-butyl4-(6-iodo-5-(4-(methoxy(methyl)amino)-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate

Into a solution of(R)-3-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-iodopyrimidin-5-yl)butanoicacid (100 g, 210 mmol) in tetrahydrofuran (700 mL) was added1,1′-carbonyldiimidazole (40.9 g, 252 mmol) in portions. The reactionmixture was stirred at 20° C. for 1 h and cooled to 5° C.N,O-dimethylhydroxyamine hydrochloride (41.0 g, 420 mmol) was added inportions followed by N-methylmorpholine (6.94 mL, 63.0 mmol). Themixture was stirred at 5° C. for about 1 h, slowly warmed up to roomtemperature, and stirred for 24 h. Saturated aqueous ammonium chloride(500 mL) and water (150 mL) were added to get a clear phase separation.The organic layer was washed with saturated aqueous ammonium chloride(500 mL) and brine (200 mL). The residual water was azeotroped off toless than 500 ppm by co-evaporation with tetrahydrofuran. The product,as a solution in tetrahydrofuran was used for the next step withoutfurther purification or isolation (weight assay yield: >99%. ¹H NMR (300MHz, CDCl₃) δ 8.23 (s, 1H), 3.84 (ddq, J=9.0, 7.2, 5.1 Hz, 1H), 3.72 (s,3H), 3.61-3.57 (m, 4H), 3.42 (dd, J=16.5, 9.0 Hz, 1H), 3.25-3.21 (m,4H), 3.17 (s, 3H), 2.76 (dd, J=16.5, 5.1 Hz, 1H), 1.47 (s, 9H), 1.47 (d,J=7.2 Hz, 3H). HRMS calcd. For C₁₉H₃₁IN₅O₄ [M+H]+: 520.1415. found520.1413.

Example 6

(R)-tert-butyl4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate

Method A:

A solution of (R)-tert-butyl4-(6-iodo-5-(4-(methyl(phenyl)amino)-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate(109 g, 210 mmol) in tetrahydrofuran (600 mL) was purged with nitrogenfor 30 min. Isopropyl magnesium chloride solution (159 mL, 210 mmol,1.32 M in tetrahydrofuran) was added dropwise at −15° C. The mixture wasstirred at −10° C. for 1 h and slowly transferred into a cold 20 wt %aqueous ammonium chloride (600 mL) with stirring while maintaining theinternal temperature below 10° C. The organic layer was then washed withsaturated aqueous ammonium chloride (500 mL). Tetrahydrofuran wasdistilled off at reduced pressure below 40° C. Methyl tert-butyl ether(350 mL) was slowly added while maintaining the internal temperaturebetween 35° C. and 40° C., followed by heptane (350 mL). The mixture wasslowly cooled down to 20° C. and product gradually precipitated outduring the process. The slurry was filtered and the cake was dried at40° C. under vacuum to give a gray solid (52.3 g, 75% yield over twosteps). ¹H NMR (300 MHz, CDCl₃) δ 8.73 (s, 1H), 3.92-3.83 (m, 2H),3.73-3.49 (m, 7H), 2.96 (dd, J=16.5, 7.2 Hz, 1H), 2.33 (dd, J=16.5, 1.8Hz, 1H), 1.50 (s, 9H), 1.32 (d, J=6.9 Hz, 3H). HRMS calcd. ForC₁₇H₂₅N₄O₃ [M+H]+: 333.1921. found 333.1924.

Method B:

Table 1, shows example substrates that were used for preparing(R)-tert-butyl4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate,according to the above procedure. The compound in the Substrate columnwas used in place of (R)-tert-butyl4-(6-iodo-5-(4-(methyl(phenyl)amino)-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylatein the above procedure, the conditions of the reaction are shown in theScale and Conditions column, with all other conditions beingsubstantially the same. The amount shown in the Yield column representsthe area percentage of the peak of cyclized product in the crudereaction mixture as measured by HPLC-MS. The amount shown in theparenthesis represents the isolated yield. The final product,(R)-tert-butyl4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate,was not isolated from the below reactions.

TABLE 1 Scale and Example Number Substrate Conditions Yield % 6.1

500 mg; −20° C. >95 (88) 6.2

500 mg; −20° C. 88 6.3

500 mg; −20° C. 85 (83) 6.4

500 mg; −20° C. 67 6.5

500 mg; −20° C. 90 (33) 6.6

i-PrMgCl•LiCl (2.2 equiv); room temperature; 42 hr 26 6.7

i-PrMgCl•LiCl (2.2 equiv); room temperature; 3 hr 15 6.8

n-BuLi (4.0 equiv) THF, −78° C., 60 min, quenched with sat'd. NH₄Cl at−78° C. 78 6.9

n-BuLi (3.0 equiv) THF, −78° C., 30 min, quenched with MeOH at −78° C.45

Experiments described in Examples 1 through 6a were carried out inkilogram scales with comparable or better yields obtained.

All patents, patent applications, documents, and articles cited hereinare herein incorporated by reference in their entireties.

We claim:
 1. A process comprising cyclizing a compound of formula II:

or a salt thereof, to form a compound of formula I

or a salt thereof, wherein: R¹ is hydrogen or an amino protecting group;R² is —CN, —COOR^(a) or —CONR^(a)R^(b); R^(a) and R^(b) areindependently hydrogen, —OR^(c), substituted or unsubstituted C₁₋₁₂alkyl, substituted or unsubstituted C₂₋₁₂ alkenyl, substituted orunsubstituted C₂₋₁₂ alkynyl, substituted or unsubstituted C₃₋₈cycloalkyl, substituted or unsubstituted phenyl or substituted orunsubstituted 3 to 12 membered heterocyclyl; or R^(a) and R^(b) aretaken together with the atom to which they are attached to form a 3-7membered heterocyclyl; R^(c) is independently hydrogen or optionallysubstituted C₁₋₁₂ alkyl; and M is Li or Mg.
 2. The process of claim 1,further comprising, contacting a compound of formula III, or a saltthereof, with a magnesium or lithium metalating agent:

wherein R³ is bromo or iodo; to form the compound of formula I or a saltthereof.
 3. The process of claim 2, further comprising contacting acompound of formula IV:

or a salt thereof, with a compound

or a salt thereof, wherein Lv is a leaving group, and each R³ isindependently iodo or bromo, to form the compound of formula III or asalt thereof.
 4. The process of claim 3, further comprising brominatingor iodinating a compound of formula V:

or a salt thereof, wherein R⁴ is —Cl or —OH, to form the compound offormula IV or a salt thereof.
 5. The process of claim 1, wherein M isMg.
 6. The process of claim 2, wherein the metalating agent is analkylmagnesium halide.
 7. The process of claim 2, wherein the metalatingagent is iPrMgCl.
 8. The process of claim 1, wherein R¹ is —C(O)OR^(d),wherein R^(d) is hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted phenyl or substituted or unsubstituted heterocyclyl. 9.The process of claim 1, wherein R¹ is a Boc group.
 10. The process ofclaim 1, wherein R² is —COOR^(a) or —CONR^(a)R^(b).
 11. The process ofclaim 1, wherein R² is —C(O)N(R^(a))OR^(c).
 12. The process of claim 1,wherein R² is —C(O)N(CH₃)OCH₃.
 13. The process of claim 2, wherein R³ isiodo.
 14. The process of claim 3, wherein Lv is hydrogen and R¹ is anamino protecting group.
 15. The process of claim 1, wherein R¹ isselected from acetyl, trifluoroacetyl, phthalimidyl, benzyl,triphenylmethyl, benzylidenyl, p-toluenesulfonyl, p-methoxybenzyl,tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl and carbobenzyloxy.